Double stranded RNA is generated during viral replication. The synthetic analogue poly IC is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly IC preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly IC (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly IC of less then 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNβ nor brain transcription of Irf7 were significantly induced by LMW poly IC, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNβ binding of IFNAR1. In aged animals, poly IC induced exaggerated IL-6, IL-1β and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.The cartilage degeneration that accompanies subchondral bone necrosis plays an important role in the development of osteonecrosis of femoral head (ONFH). To better understand the molecular basis of cartilage degradation in ONFH, we compared the proteomic profiles of ONFH cartilage with that of fracture control.
Hip cartilage samples were collected from 16 ONFH patients and 16 matched controls with femoral neck fracture. Proteomics analysis was conducted using tandem mass tag-based quantitation technique. Gene ontology (GO) analysis, KEGG pathway and protein-protein interaction analysis were used to investigate the functions of the altered proteins and biological pathways. Differentially expressed proteins including alpha-2-HS-glycoprotein (AHSG) and Cytokine-like protein 1 (Cytl1) were validated by Western blot (WB) and immunohistochemistry (IHC).
303 differentially expressed proteins were identified in ONFH cartilage with 72 up-regulated and 231 down-regulated. Collagen turnover, glycosaminoglycan biosynthesis, metabolic pathways, and complement and coagulation cascades were significantly modified in ONFH cartilage. WB and IHC confirmed the increased expression of AHSG and decreased expression of Cytl1 in ONFH cartilage.
Our results reveal the implication of altered protein expression in the development of ONFH, and provide novel clues for pathogenesis studies of cartilage degradation in ONFH.
Our results reveal the implication of altered protein expression in the development of ONFH, and provide novel clues for pathogenesis studies of cartilage degradation in ONFH.Macrophages play an important part in the pathogenesis of osteoarthritis (OA). Our objective was to determine the effects of α-defensin-1 on macrophage polarization and consequently OA.
OA synovial tissue and synovial fluid were assessed for the presence of M1 (CD68CD16CD206) and M2 (CD68CD206CD16) macrophages by flow cytometry. M0, M1, and M2 macrophages were co-cultured with OA chondrocytes to determine their influence on chondrogenic phenotype. Polarization of THP-1 activated monocytes from M1 to M2 in response to α-defensin-1 was evaluated by flow cytometry, RT-PCR and RNA sequencing. Effects of intra-articular α-defensin-1 in vivo were evaluated in a rat meniscal/ligamentous injury (MLI) model.
The quantity of M1 exceeded M2 polarized macrophages in human OA synovial tissue (mean difference 26.1% [13.6-38.6%], P&lt;0.001) and fluid (mean difference 10.5% [5.0-16.1%], P=0.003). M1 to M2 polarization in vitro was most effectively promoted with 10ng/mL α-defensin-1. Compared with untreated macrophages, the α-defensin-1 polarized macrophages modified co-cultured OA chondrocytes from a pro-catabolic state to a pro-anabolic (regenerative-like) state based on expression of COL2A1, ACN, MMP3, MMP13 and ADAMTS5. Intra-articular α-defensin-1 decreased severity of cartilage damage and synovitis in the MLI rat model. RNAseq analyses suggested insulin and Toll-like receptor signaling pathways in the chondroprotective α-defensin-1 mechanism of action.
α-defensin-1 promotes M1 to M2 macrophage polarization in vitro, has beneficial effects on chondrocytes indirectly via M2 macrophage polarization, and attenuates the severity of OA in vivo, suggesting it might be a candidate treatment for OA.
α-defensin-1 promotes M1 to M2 macrophage polarization in vitro, has beneficial effects on chondrocytes indirectly via M2 macrophage polarization, and attenuates the severity of OA in vivo, suggesting it might be a candidate treatment for OA.To report the efficacy of photodynamic therapy (PDT) for management of retinal hemangioblastoma.
Retrospective case series.
Seventeen patients with retinal hemangioblastoma treated with PDT.
The medical records of 17 patients with retinal hemangioblastoma treated with PDT were reviewed, and treatment outcomes were assessed. Photodynamic therapy was performed with 6 mg/mbody surface area of verteporfin infused intravenously over 10 minutes activated by 50 J/cmlaser light at 689 nm for 83 or 166 seconds.
Tumor control, subretinal and intraretinal fluid resolution, and visual outcome.
Eighteen retinal hemangioblastomas in 17 eyes were treated with PDT. Median patient age was 31 years (mean, 36 years; range, 7-66 years), and median follow-up was 51 months (mean, 61 months; range, 2-144 months). https://www.selleckchem.com/products/sirpiglenastat.html Genetic testing confirmed von Hippel-Lindau disease in 8 of 17 patients (47%). The tumors were unilateral in all patients and unifocal in most patients (n= 13/17 [76%]). The tumor median basal diameter was 3.